Filaggrin is a highly charged, cationic protein that aids aggregation and subsequent disulfide bonding of keratin filaments. It is derived from profilaggrin, a large (4400 kD) phosphorylated precursor expressed as keratohyalin granules in the granular layer of the epidermis. During the transition from the granular layer to the stratum coneum, profilaggrin is converted to filaggrin by site-specific proteolysis and dephosphorylation. In addition to profilaggrin processing to filaggrin, the transition from a granular cell to a corneocyte is characterized by the degradation of the nucleus and other organelles, assembly of a cornified envelope, and reorganization of the keratin intermediate filament network into a two dimensional sheet. Fillagrin plays a critical role in the generation and maintenance of a flexible and hydrated stratum corneum and its hydrolysis is carefully regulated to generate free amino acids that form a major part of the natural moisturizing factors (NMF). The transition from a granular precursor, profilaggrin, to a diffusely distributed protein happens quickly at the granular to stratum corneum transition in response to an initiating signal which is not yet known. That profilaggrin is expressed as a precursor, rather than a mature protein, suggests that filaggrin expression must be regulated to prevent cytotoxic effects. Many inflammatory skin conditions are characterized by attenuation of the granular layer with concomitant parakeratosis, i.e. retained nuclei in the keratinocytes of the stratum corneum. While the signals that are disrupting terminal differentiation in these inflammatory conditions may be disparate, a common final theme is loss of the granular layer with subsequent incomplete terminal differentiation. In conditions where profilaggrin is decreased, such as atopic dermatitis, or essentially absent, as in ichthyosis vulgaris, the quality of the stratum corneum is compromised due to the inability of an NMF-depleted stratum corneum to remain hydrated under the desiccating action of the environment.
The natural moisturizing factors (NMF) perform an important function in maintaining the moisture content of the stratum corneum. It has been reported that amino acids forming the principal constituents of NMF are produced by the proteoliticaly cleaved filaggrin originating from keratohyalin granules. Filaggrin is a protein composed of 317 amino acids. Since it was clarified that amino acids forming the principal constituents of NMF are derived from filaggrin, investigations on the relation of morbid states exhibiting a dry skin to filaggrin have been carried forward. In recent years, it has been clarified that the amino acid content of the stratum corneum is reduced in a dry skin as seen in senile xerosis, atopic diseases and the like, and that the expression of filaggrin in such a dry skin is decreased. Moreover, it is well known that skin troubles such as rough skin are caused by a dry environment.
Filaggrin gene plays a role in building up the barrier layers of the skin and mutations in this gene lead to conditions such as eczema. Filaggrin is an abundant protein in the outermost layers of the skin and is produced by the Filaggrin gene. Filaggrin's function is to help produce the impermeable skin barrier layers present at the skin's outermost surface and to keep these hydrated. The skin's inherent barrier function is akin to plastic or cling film—it acts to prevent water loss from the skin and importantly, to protect the body from foreign materials in the environment, such as allergens. Lack of an intact skin barrier leads to allergens entering the body where they produce a range of allergic responses that include eczema, asthma, hay fever and other allergies.
DNA-RNA and RNA-RNA hybridization are important to many aspects of nucleic acid function including DNA replication, transcription, and translation. Hybridization is also central to a variety of technologies that either detect a particular nucleic acid or alter its expression. Antisense nucleotides, for example, disrupt gene expression by hybridizing to target RNA, thereby interfering with RNA splicing, transcription, translation, and replication. Antisense DNA has the added feature that DNA-RNA hybrids serve as a substrate for digestion by ribonuclease H, an activity that is present in most cell types. Antisense molecules can be delivered into cells, as is the case for oligodeoxynucleotides (ODNs), or they can be expressed from endogenous genes as RNA molecules. The FDA recently approved an antisense drug, VITRAVENE™ (for treatment of cytomegalovirus retinitis), reflecting that antisense has therapeutic utility.